1. Field of the Invention
The present invention relates to novel halogenated derivatives of 2,3'-O-cyclocytidine compounds and to a process for production thereof.
2. Brief Description of the Prior Art
Mizuno et al. (Tet. Lett., 4579-4584 (1965)), the contents of which are incorporated herein by reference, teach the production of 2,3'-O-cyclocytidine via a six step process which includes the production of 3'-O-mesylcytidine via a four step process from N.sup.4 -acetylcytidine. This corresponds to a five step process, overall, if cytidine is used as the starting material. Thus, it is not surprising that the overall yield of 3'-O-mesylcytidine produced in this manner is less than 10% (even this low yield assumes theoretical yields for two of the five steps where yield was unreported). As taught in Mizuno et al. (Tet. Lett., 4579-4584 (1965)), 2,3'-O-cyclocytidine is produced from 3'-O-mesylcytidine as a crystalline freebase. Specifically, the last step in the process comprises reacting 3'-O-mesylcytidine with an excess of sodium t-butoxide to produce 2,3'-O-cyclocytidine. Unfortunately, the first step in the process involves conversion of N.sup.4 -acetylcytidine (NOTE: this was obtained from cytidine in only a 65% yield) to 2',5'-di-O-trityl-N.sup.4 -acetylcytidine in only a 20% yield. Accordingly, the process of Mizuno et al. is deficient in that it requires an onerous number of steps to produce 2,3'-O-cyclocytidine and, when produced, 2,3'-O-cyclocytidine is obtained in a relatively low yield of less than 8.5% (even this low yield assumes theoretical yields for two of the six steps where yield was unreported).
Further, Doerr et al. (J.Org.Chem., 32, 1462-1471 (1967)), the contents of which are incorporated herein by reference, found it surprising that Mizuno et al. reported isolating 2,3'-O-cyclocytidine in neutral form.
These problems of low yields of 2,3'-O-cyclocytidine has been addressed by Karimian et al. in International patent application S.N. PCT/CA91/00078 (published Sep. 19, 1991 as WO 91/13901), the contents of which are incorporated herein by reference. Specifically, Karimian et al. teach that the hydrochloride salt of 2,3'-O-cyclocytidine, Formula II, ##STR2## may be produced in relatively high yields by a reaction comprising the step of intramolecular rearrangement of a compound having the formula ##STR3## wherein Ts is a tosyl group, followed by reaction with hydrogen chloride, to produce the compound of Formula II.
As is known in the art, 2,3'-O-cyclocytidine (including its salts, analogues and derivatives) has utility as an antineoplastic and an antiviral agent.
There is an ongoing need to develop compounds related to 2,3'-O-cyclocytidine which have similar or enhanced activity as antineoplastic and antiviral agents.